Composition based on lipid lamellar vesicles incorporating at least a dhea compound

ABSTRACT

The present invention relates to a composition comprising: a dispersion, in an outer aqueous phase, of vesicles formed by lipid lamellar phases comprising at least one amphiphilic lipid and encapsulating an inner hydrophilic phase, the said lamellar phases not comprising succinic and/or hemisuccinic derivatives, and at least one DHEA-based compound included in the said lamellar phases. The incorporation of the DHEA-based compound into the lamellar phases of vesicles makes it possible to avoid its recrystallization in the outer aqueous phase and to improve its bioavailability.

The invention relates to a composition comprising vesicles formed fromlipid lamellar phases containing at least one DHEA-based compound. Theinvention also relates to a process for preparing this composition.

For the purposes of the invention, the term “DHEA-based compound” meansDHEA itself, DHEA precursors or DHEA derivatives.

Many patents exist describing cosmetic or dermatological compositionsfor topical application comprising dehydroepiandrosterone and/or itsderivatives. For example, patent U.S. Pat. No. 5,989,568 describes theuse of dehydroepiandrosterone sulphate in a topical composition fortreating wrinkles and fine lines and/or for combating cutaneous and/orsubcutaneous slackening and/or for reviving the radiance of the skin.

DHEA, or dehydroepiandrosterone, is a natural steroid producedessentially by the adrenal glands. Exogenous DHEA, administeredtopically or orally, is known for its capacity to promote keratinizationof the epidermis (JP-07 196 467) and to treat dry skin by increasing theendogenous production and the secretion of sebum, thus reinforcing theskin's barrier effect (U.S. Pat. No. 4,496,556). The use of DHEA forovercoming dermal atrophy by inhibiting the loss of collagen and ofconnective tissue has also been described in patent U.S. Pat. No.5,843,932. Finally, the Applicant has demonstrated the capacity of DHEAto combat the weathered appearance of the skin (FR 00/00349) and tomodulate the pigmentation of the skin and the hair (FR 99/12773). Theseproperties of DHEA make it a candidate of choice as an anti-ageingactive agent.

Among the DHEA metabolites, particular attention has been paid in recentyears to 7α-hydroxy DHEA. Specifically, it has been demonstrated thatthis metabolite, which does not have the hormonal activity of DHEA,makes it possible to increase the proliferation of fibroblasts and theviability of human keratinocytes, and has free-radical-scavengingeffects (WO 98/40074). It has also been demonstrated on rats (WO00/28996) that 7α-hydroxy DHEA increases the thickness of the dermis andthe elastin and collagen content of the skin. It has thus been suggestedto use this DHEA metabolite to prevent and/or treat the harmful effectsof UV on the skin, to combat wrinkles and to increase the firmness andtonicity of the skin.

However, DHEA-based compounds have the drawback of being very sparinglysoluble in cosmetic solvents, and of crystallizing in the presence of anaqueous phase. This results in a more or less pronounced loss ofefficacy of these compositions depending on the degree ofcrystallization, which is counter to the desired objective.

Furthermore, DHEA-based compounds have better bioavailability in theskin when they are in dissolved form in cosmetic supports, andfurthermore at high levels, than when they are in crystalline form witha poorly controlled crystal size.

For the purposes of the patent application, the term “bioavailability”means the molecular penetration of the active agent under considerationinto the live layers of the skin and in particular of the epidermis. Itwill be sought to enable the penetrated concentration to be as high aspossible, so as to increase the amount of active agent arriving as faras the live layers of the skin.

It is possible to dissolve DHEA-based compounds at 25° C. in certainsolvents such as propylene glycol, liposoluble screening agents or2-alkyl alkanols, for example, but, to do this, it is necessary to havevery high concentrations of solvents in order to dissolve large amountsof DHEA-based compounds. Now, since these solvents are preferably oily,it will rather be sought to limit their content in the final compositionin order to have the most acceptable cosmetic feel possible and also tolimit any problems of tolerance.

There is thus still a need to dissolve DHEA-based compounds in aphysiologically acceptable vehicle.

The Applicant has now discovered that DHEA and/or its derivatives and/orits precursors can be introduced into compositions as constituents oflipid lamellar phases of vesicular type encapsulating a hydrophilicphase. These vesicles may be either niosomes of the type described inpatent applications EP-958 856, EP-582 503, EP-455 528 or EP-43327, orliposomes of standard type. DHEA and/or its derivatives and/orprecursors become, in this type of structure, one of the constituents ofthe lamellar phases.

It is known to those skilled in the art that cholesterol can be used toreinforce the leaktightness of the wall of such vesicles. The Applicanthas now found, surprisingly, that it is possible, in the constitution ofthe lipid lamellar phases, to replace cholesterol with at least oneDHEA-based compound.

These compounds, although having a structure similar to cholesterol, aremore polar: they are characterized by solubility parameters revealing apolarity of the DHEA-based compounds that is higher than that ofcholesterol.

For the purposes of the invention, the term “solubility parameters”means the Hansen solubility parameters δ_(d), δ_(p) and δ_(h). Theseparameters are defined in the document S. Paint Technology 30, 195(1967) “The Three Dimensional Solubility Parameter—Key to PaintComponent Affinities”.

The solubility parameters of cholesterol, DHEA and its analogues arepresented in Table 1 below. TABLE 1 Cholesterol DHEA 7-Keto-DHEA7a-OH-DHEA δ_(a)* 7.31 9.95 10.72 13.21*δ_(a) = [(δ_(p))² + (δ_(h))²]^(1/2)

Given these differences in polarity, the pure and simple replacement ofcholesterol with one of these molecules was not obvious. Specifically,these polarities imply a higher affinity with water than in the case ofcholesterol and induce higher Ostwald maturation sensitivity (Kabalnovet al., J. Colloid and Interface Sci. 118 (1987) 590-597), which shouldtherefore lead to rapid recrystallization of the DHEA-based compounds inthe continuous phase of the compositions containing them.

The introduction of a DHEA-based compound is performed by replacing allor some of the cholesterol with the said DHEA-based compound. The lattercompound is then intimately associated with the other lipidsconstituting the lamellar phase of the vesicles (hydrogenated ornon-hydrogenated lecithin, nonionic surfactants capable of forminglamellar phases when they are combined with cholesterol, as described inpatents EP 958 856, EP 582 503, EP 455 528 and EP 43327, and ionicsurfactants intended to stabilize the vesicles obtained). They do notrecrystallize in the continuous medium which is water and in which theyare insoluble.

Admittedly, a person skilled in the art knows the formulation ofliposomes based on a 5β-steroid.

Thus, international patent application WO-97/13500 describes liposomescomprising a lipid or a lipid compound and a 5β-steroid, DHEA or anorganic acid derived from a 5β-steroid or DHEA. The vesicles describedin the said patent application are based on an α-tocopherylhemisuccinate salt prepared beforehand, and also on a Tris salt ofcholesteryl hemisuccinate, which is also prepared beforehand. Thesevesicles are especially intended for treating obesity and/or diabetesand/or hypercorticoidism. The preparation of these vesicles is long andcomplex and does not allow large-scale exploitation.

One subject of the present invention is thus a composition comprising:

-   -   a dispersion, in an outer aqueous phase, of vesicles formed by        lipid lamellar phases comprising at least one amphiphilic lipid        and encapsulating an inner hydrophilic phase and dispersed in an        outer aqueous phase, the said lamellar phases not comprising        succinic and/or hemisuccinic derivatives, and    -   at least one DHEA-based compound included in the said lamellar        phases.

The incorporation of the said DHEA-based compound into the lamellarphases of the vesicles allows it to be made available in a dissolvedform and to efficiently avoid its crystallization in the aqueous phase.In addition, the vesicles according to the invention promote thebioavailability of the said DHEA-based compound in the skin. Finally,the gradual degradation of the vesicles according to the inventionallows a controlled release of the said DHEA-based compound that theycontain.

For the purposes of the patent application, the term “dissolved form”means a dispersion in molecular form in a lyotropic phase of liquidcrystal type, of lamellar or hexagonal type, no crystallization of theactive agent being visible to the naked eye or by cross-polarizedoptical microscopy.

The DHEA-based compounds that may be used according to the invention arechosen from DHEA itself, DHEA precursors and DHEA derivatives.

As DHEA precursors that may be used according to the invention, mentionmay be made of its biological precursors that may be converted into DHEAduring metabolism, and also its chemical precursors that may beconverted into DHEA by exogenous chemical reaction. Examples ofbiological precursors are Δ5-pregnenolone, 17α-hydroxypregnenolone and17α-hydroxypregnenolone sulphate, this list not intended to be limiting.Examples of chemical precursors are sapogenins and derivatives thereofsuch as diosgenin (or 5-spirostene-3β-ol), hecogenin, hecogenin acetate,smilagenin and sarsapogenin, tigogenin, yamogenin and yuccagenin, andalso natural extracts containing them, in particular fenugreek andextracts of Dioscorea plants such as extract of wild yam, this list notintended to be limiting.

AS DHEA derivative that may be used according to the invention, mentionmay be made of both its metabolic derivatives and its chemicalderivatives.

Metabolic derivatives that may especially be mentioned includeA5-androstene-3,17-diol and Δ4-androstene-3,17-dione, and also 7α-OHDHEA, 7β-OH DHEA, 11α-OH DHEA and 7-keto-DHEA, this list not intended tobe limiting. 7α-OH DHEA is preferred for use in the present invention. Aprocess for preparing this compound is described in particular in patentapplications FR 2 771 105 and WO 94/08588.

Chemical derivatives that may especially be mentioned include DHEA saltsand in particular water-soluble salts such as DHEA sulphate. Mention mayalso be made of esters such as hydroxycarboxylic acid esters of DHEA,described in particular in U.S. Pat. No. 2,736,537 or other esters suchas DHEA salicylate, DHEA acetate, DHEA valerate (or n-heptanoate) andDHEA enanthate. Mention may also be made of DHEA derivatives (DHEAcarbamates, DHEA 2-hydroxymalonate esters and DHEA amino acid esters)described in patent application FR 00/03846 in the name of theApplicant. 3-Alkyl esters of 7-keto-DHEA, for example3-acetoxy-7-keto-DHEA, may also be mentioned.

Other chemical DHEA derivatives that are suitable for use in the presentinvention are the derivatives of formula (1):

in which:

-   R₁ and R₂ are chosen independently from:    -   a saturated or unsaturated, linear, branched or cyclic C₁-C₁₂        alkyl group optionally containing one or more hetero atoms, and        optionally substituted with one or more groups chosen from —OR′        and/or —SR′ and/or —COOR′ and/or —NR′R′ and/or halogen and/or        sulphate and/or phosphate and/or aryl and/or heterocycle, the        said heterocycle advantageously being chosen from an indole, a        pyrimidine, a piperidine, a morpholine, a pyran, a furan, a        piperazine and a pyridine;    -   an alkylcarbonyl group, the C₁-C₂₄ alkyl portion of which is        saturated or unsaturated, linear, branched or cyclic, and        optionally substituted with one or more groups chosen from —OR′        and/or —SR′ and/or —COOR′ and/or —NR′R′ and/or halogen and/or        sulphate and/or phosphate and/or aryl and/or heterocycle, the        said heterocycle advantageously being chosen from an indole, a        pyrimidine, a piperidine, a morpholine, a pyran, a furan, a        piperazine and a pyridine;    -   an arylcarbonyl group, preferably a phenylcarbonyl group, or an        arylalkylcarbonyl group, preferably a benzylcarbonyl group,        optionally substituted with one or more groups —OR′ and/or —SR′        and/or —COOR′ and/or —NR′R′ and/or halogen and/or aryl and/or        heterocycle;    -   a group O═P(OH)OR′;    -   a group (O)₂SOR′;    -   a trialkylsilyl group (SiR′₃) in which the 3 groups R′ may be        identical or different;    -   a carbonyloxyalkyl group (R′OCO);    -   a carbonylaminoalkyl group (R′NHCO); in which R′ is chosen from        a hydrogen atom, a saturated or unsaturated, linear, branched or        cyclic C₁-C₁₂ and preferably C₁-C₆ alkyl group optionally        containing one or more hetero atoms, optionally functionalized        with one or more groups —OR″, —COOR″, halogen, —NR″R″; or with        an aryl group, preferably a phenyl group, optionally        functionalized with one or more groups —OR″, —COOR″, halogen or        —NR″R″;-   R″ representing a hydrogen atom or a saturated or unsaturated,    linear, branched or cyclic alkyl chain, preferably of C₁-C₆,-   it being understood that, in each of the groups —NR′R′ and —NR″R″,    the substituents R′ or R″, respectively, are identical or different.

Among the derivatives of formula (1) that may be mentioned in particularare 7-OH-DHEA diesters and more preferably3-O-acetyl-7-benzoyloxydihydroepiandro-sterone, which is especiallyavailable from the company Gattefosse under the trade name3-acetoxy-7-benzoate DHEA.

The DHEA-based compound(s) may represent from 0.1% to 50% by weight andpreferably from 1% to 25% by weight of the lipid compositionconstituting the membrane of the vesicles, i.e. the lipid lamellarphases.

The vesicles according to the invention are preferably formed by, orcomprise, from 1 to 25 leaflets of substantially concentric lamellarphases of bimolecular type.

These leaflets are obtained from lipids that have both the property offorming mesomorphic phases, the state of organization of which isintermediate between the crystalline state and the liquid state, and ofswelling in the presence of an aqueous solution to form the saidlamellar phases which will give, with stirring, the vesicles dispersedin the aqueous phase.

The vesicles according to the invention are lipid lamellar vesicles withan aqueous core, i.e. encapsulating a hydrophilic phase, which is theinner hydrophilic phase. These vesicles may be either niosomes of thetype described in patent application EP 0 582 503, the teaching of whichis incorporated herein by reference, or the like, or liposomes ofstandard type.

In the case of niosomes, the lamellar phases comprise at least onenonionic amphiphilic lipid, chosen from optionally oxyethylenated alkylor polyalkyl esters of polyol, and optionally oxyethylenated polyolethers, with a melting point of at least 40° C.

Nonionic amphiphilic lipids that are suitable for use in the presentinvention are especially glycolipids of natural or synthetic origin (forexample cerebrosides), or mixtures of polyol esters of at least one acidwith a saturated hydrocarbon-based chain containing at least 14 carbonatoms, and also polyol ethers of at least one alcohol with a saturatedhydrocarbon-based chain containing at least 14 carbon atoms.

The term “mixtures of esters” means not only mixtures of pure esters ofdifferent chemical families, but also any product containing severalchemically pure polyol esters of the same family in variableproportions, such as polyglycerol esters comprising a random number ofglycerol units.

The nonionic amphiphilic lipid may thus consist of a mixture of estersof at least one polyol chosen from the group formed by polyethyleneglycol comprising from 1 to 60 ethylene oxide units, sorbitan, sorbitanbearing 2 to 60 ethylene oxide units, glycerol bearing 2 to 30 ethyleneoxide units, polyglycerols comprising 2 to 15 glycerol units, sucroses,glucoses bearing 2 to 30 ethylene oxide units, and at least one fattyacid comprising a saturated or unsaturated, linear or branched C₁₄-C₂₀hydrocarbon-based chain.

As polyol ethers that may be used according to the invention, mentionmay be made of:

-   -   linear or branched polyglycerol ethers having the respective        formulae        R—(OCH₂—CH(OH)—CH₂)n-OH  (I)        and        R—(O—CH₂—CH(CH₂OH))n-OH  (II)        in which n is an integer between 1 and 6, preferably equal to 2,        and R is a radical chosen from:    -   (a) a linear or branched, saturated or unsaturated aliphatic        chain containing from 14 to 30 carbon atoms, such as a        tetradecyl or hexadecyl radical or the alkyl radical of oleyl        alcohol or of isostearyl alcohol;    -   (b) a hydrocarbon-based radical of lanolin alcohol;    -   (c) a 2-hydroxyalkyl residue of a (-diol, the hydrocarbon-based        chain of which contains at least 14 carbon atoms; and    -   polyoxyethylenated fatty alcohols, such as oleyl alcohol        oxyethylenated with 10 mol (“Brij 96” product sold by the        company ICI Atlas).

Moreover, with the aim of improving the stability of the niosomes asdescribed above, the lamellar phases may also comprise an ionicamphiphilic lipid. This lipid may be chosen from anionic lipids andcationic lipids.

The anionic amphiphilic lipids that are suitable for use in theinvention may be:

-   -   neutralized anionic lipids, preferably chosen from alkali metal        salts of dicetyl phosphate and of dimyristyl phosphate, in        particular the sodium and potassium salts, alkali metal salts of        phosphatidic acid, in particular the sodium salt, the alkali        metal salts of cholesteryl sulphate, in particular the sodium        salt, alkali metal salts of cholesteryl phosphate, in particular        the sodium salt, salts of lipoamino acids such as monosodium and        disodium acylglutamates, more particularly the disodium salt of        N-stearoyl-L-glutamic acid sold under the name Acylglutamate        HS21 by the company Ajinomoto,    -   amphoteric lipids, preferably phospholipids, in particular pure        soybean phosphatidylethanolamine;    -   alkylsulphonic derivatives, in particular the compounds of        formula:        in which R represents a C₁₂ to C₂₂ hydrocarbon-based radical, in        particular the C₁₆H₃₃ and C₁₈H₃₇ radicals, and M is an alkali        metal, preferably sodium.

The cationic amphiphilic lipids that may be used in the vesicles of theinvention as ionic amphiphilic lipids may be chosen more particularlyfrom the group formed by quaternary ammonium salts and fatty amines andsalts thereof.

Among the ammonium salts that are particularly suitable for use in theinvention, mention will be made of:

-   -    those represented by the general formula (II) below: in which        the radicals R₁ to R₄, which may be identical or different,        represent a linear or branched aliphatic radical containing from        1 to 30 carbon atoms, or an aromatic radical such as aryl or        alkylaryl. The aliphatic radicals can comprise hetero atoms such        as, in particular, oxygen, nitrogen, sulphur or halogens. The        aliphatic radicals are chosen, for example, from alkyl, alkoxy,        polyoxy(C₂-C₆)alkylene, alkylamide,        (C₁₂-C₂₂)alkylamido(C₂-C₆)alkyl, (C₁₂-C₂₂)alkylacetate and        hydroxyalkyl radicals containing from 1 to 30 carbon atoms        approximately; X is an anion chosen from the group formed by        halides, phosphates, acetates, lactates, (C₂-C₆)alkylsulphates        and alkyl or alkylarylsulphonates. Quaternary ammonium salts of        formula (II) which are preferred, on the one hand, are        tetraalkylammonium chlorides such as, for example,        dialkyldimethylammonium or alkyltrimethylammonium chlorides, in        which the alkyl radical contains from 12 to 22 carbon atoms        approximately, in particular behenyltrimethylammonium chloride,        distearyldimethylammonium chloride, cetyltrimethylammonium        chloride or benzyldimethylstearylammonium chloride, or        alternatively, on the other hand,        stearamidopropyl-dimethyl(myristyl acetate)ammonium chloride        sold under the name Ceraphyl 70 by the company Van Dyk.    -   quaternary ammonium salts of imidazolinium, for example        represented by the formula (III) below:    -    in which R₅ represents an alkenyl or alkyl radical containing        from 8 to 30 carbon atoms, for example a tallow fatty acid        derivative; R₆ represents a hydrogen atom, an alkyl radical        containing from 1 to 4 carbon atoms or an alkenyl or alkyl        radical containing from 8 to 30 carbon atoms; R₇ represents an        alkyl radical containing from 1 to 4 carbon atoms; R₈ represents        a hydrogen atom or an alkyl radical containing from 1 to 4        carbon atoms; X is an anion chosen from the group formed by        halides, phosphates, acetates, lactates, alkyl sulphates and        alkyl or alkylaryl sulphonates. Preferably, R₅ and R₆ denote a        mixture of alkenyl or alkyl radicals containing from 12 to 21        carbon atoms, for example tallow fatty acid derivatives, R₇        denotes a methyl radical and R₈ denotes hydrogen. Such a product        is sold, for example, under the name Rewoquat W75 by the company        Rewo.    -   diquaternary ammonium salts represented by the formula (IV)        below:    -    in which R₆ denotes an aliphatic radical containing from 16 to        30 carbon atoms approximately; R₇, R₈, R₉, R₁₀ and R₁₁, which        may be identical or different, are chosen from hydrogen or an        alkyl radical containing from 1 to 4 carbon atoms; and X is an        anion chosen from the group formed by halides, acetates,        phosphates, nitrates and methyl sulphates. Such diquaternary        ammonium salts in particular comprise propane tallow diammonium        dichloride.

Besides the nonionic and ionic amphiphilic lipids, the lamellar phasesof the vesicles of niosomal type may also contain at least one additivechosen from sterols, fatty-chain alcohols and diols, fatty-chain aminesand quaternary ammonium derivatives thereof.

It is preferred to use cholesterol, which, besides its cosmetic and/ordermopharmaceutical activity associated with its capacity toreconstitute skin lipids, makes it possible to improve the stability ofthe vesicles by avoiding the crystallization of the surfactants withwhich it is combined. By improving the impermeability of the lamellarphases of the vesicles, cholesterol also makes it possible to increasethe power of retention of the water-soluble active agents possiblycontained in the hydrophilic phase encapsulated by the niosomes.

The lamellar phases of the vesicles of niosomal type may contain, forexample, from 35% to 90% by weight of nonionic amphiphilic lipid, from 0to 20% by weight of ionic amphiphilic lipid, from 5% to 50% by weight ofcholesterol and from 0.1% to 50% by weight of at least one DHEA-basedcompound relative to the total weight of the lipids constituting thelamellar phase.

As mentioned previously, the lipid lamellar vesicles according to theinvention may comprise not only vesicles of nonionic type such asniosomes, but also standard liposomes, comprising at least one ionicamphiphilic lipid such as a natural or synthetic phospholipid, inparticular lecithin, which is preferably hydrogenated, combined eitherwith cholesterol and optionally with an ionic surfactant, or with anoxyethylenated phytosterol comprising from 2 to 50 ethylene oxide units.

In this embodiment variant of the invention, the vesicles may comprisefrom 50% to 99% by weight of lecithin, from 50% to 1% by weight of amixture of cholesterol and of at least one DHEA-based compound, and from0 to 20% by weight of ionic surfactant, relative to the total weight ofthe lipids constituting the lamellar phase. As a variant, they maycomprise from 40% to 80% by weight of lecithin and from 20% to 60% byweight of a mixture of oxyethylenated phytosterol and of at least oneDHEA-based compound, relative to the total weight of the lipidsconstituting the lamellar phase. In both cases, the amount of DHEA-basedcompound generally represents from 0.1% to 50% of the total weight ofthe lipids constituting the lamellar phase.

The methods for manufacturing the vesicles according to the inventionare known to those skilled in the art, but the preferred methods are thefollowing:

Bangham Method

The vesicular lipids are dissolved in a mixture of organic solvents.This mixture is then placed in a round-bottomed flask and the solventsare evaporated off on a rotary evaporator under reduced pressure. Alipid film then forms. After total evaporation of the solvents, the filmis hydrated with an aqueous solution, with vigorous stirring. Thetemperature is adjusted to the melting point of the lipids. A suspensionof liposomes is then obtained. It is then possible to homogenize itusing ultrasound.

Method via Direct Hydration of the Lipids

The lipids may or may not have been preassociated (via melting or viasolvent). The lipid mixture is then introduced with vigorous stirring(for example a rotor-stator) into an aqueous solution at an adjustedtemperature. After a few minutes (generally from 5 to 90 minutes), asuspension of liposomes is obtained. What has thus been made is anaqueous dispersion of DHEA (and/or of its derivatives and/or itsprecursors), which does not recrystallize over time (at least three daysat 25° C.), since it is intimately associated with the components of thevesicular membrane.

Irrespective of the invention embodiment used (niosomes or liposomes),the lipids constituting the vesicles usually represent from 1% to 20%and preferably from 1% to 10% of the total weight of the composition.

In the composition according to the invention, the vesicles with anaqueous core described above (niosomes or liposomes) are dispersed in anaqueous dispersion phase, or outer aqueous phase, comprising aphysiologically acceptable medium, i.e. a medium that is compatible withthe skin or its integuments, and possibly with mucous and/or semi-mucousmembranes.

The aqueous dispersion phase may be gelled. Examples of gelling agentsthat may be used according to the invention include carboxyvinylpolymers (carbomer), acrylic copolymers such as acrylate/alkylacrylatecopolymers, polyacrylamides such as partially neutralized and highlycrosslinked polyacrylamidomethylpropanesulphonic acid, polysaccharides,natural gums and clays.

As a variant, the aqueous dispersion phase may comprise an oily phasedispersed in the said aqueous phase (oil-in-water emulsion) and/or mayitself be dispersed in an oily phase (water-in-oil emulsion).

As oils that may be used according to the invention, mention may be madeof animal or plant oils, natural or synthetic essential oils,hydrocarbons such as isohexadecane and liquid paraffin, halocarbons andsilicone oils.

As animal or plant oils that may be used according to the invention,mention may be made especially of animal or plant oils formed from fattyacid esters of polyols, in particular liquid triglycerides, for examplesunflower oil, maize oil, soybean oil, marrow oil, grapeseed oil, jojobaoil, sesame seed oil, hazelnut oil, fish oils, glyceryltricaprocaprylate or plant or animal oils of formula R₁COOR₂, in whichformula R₁ represents a higher fatty acid residue containing from 7 to19 carbon atoms and R₂ represents a branched hydrocarbon-based chaincontaining from 3 to 20 carbon atoms, for example purcellin oil.

As essential oils that may be used according to the invention, mentionmay be made of natural or synthetic essential oils, for instanceeucalyptus oil, lavandin oil, lavender oil, vetiver oil, Litsea cubebaoil, lemon oil, sandalwood oil, rosemary oil, camomile oil, savory oil,walnut oil, nutmeg oil, cinnamon oil, hyssop oil, caraway oil, orangeoil, geraniol oil, cade oil and bergamot oil.

As halocarbons that may be used according to the invention, mention maybe made of fluorocarbons such as fluoroamines, for exampleperfluorotributylamine, fluorohydrocarbons, for exampleperfluorodecahydronaphthalene, fluoroesters and fluoroethers.

When the vesicles according to the invention are dispersed in theaqueous phase of an oil-in-water emulsion, the said emulsion maycomprise surfactants other than those constituting the vesicles,provided that these surfactants do not dissolve the vesicles, formingmicelles.

However, according to another possibility, when the compositionaccording to the invention is in the form of an oil-in-water emulsion,it cannot contain any surfactant other than those forming the lipidlamellar vesicles. Specifically, the vesicles according to the inventionmay be capable of stabilizing a dispersion of oil droplets in theaqueous dispersion phase, without it being necessary to add a surfactantto the said aqueous phase.

Needless to say, as a variant, the composition according to theinvention may be in the form of a water-in-oil-in-water oroil-in-water-in-oil multiple emulsion in which the aqueous and oilyphases are as defined above.

The vesicles of the compositions according to the invention may contain,in a known manner, one or more active compound(s) with cosmetic and/ordermopharmaceutical activity, which, depending on their solubilitycharacteristics, may be in different locations.

If the active agents are water-soluble, they are introduced into theencapsulated hydrophilic phase of the vesicles.

If the active agents are liposoluble, they are introduced into the lipidphase constituting the membrane.

If the active agents are amphiphilic, they are distributed between thelipid phase and the encapsulated hydrophilic phase, with a partitioncoefficient that varies depending on the nature of the amphiphilicactive agent and the respective compositions of the lipid phase and ofthe encapsulated hydrophilic phase.

In a known manner, the composition according to the invention may alsocontain adjuvants that are common in cosmetics, such as preservingagents, antioxidants, solvents, fragrances, odour absorbers,neutralizers, sunscreens, polymers, emulsifiers and co-emulsifiers, anddyestuffs.

Active agents that may especially be used include depigmenting agents,emollients, moisturizers, antiseborrhoeic agents, anti-acne agents,agents for promoting regrowth of the hair, keratolytic and/ordesquamating agents, anti-wrinkle and tensioning agents, and vitamins,and mixtures thereof.

The compositions according to the invention may also contain at leastone UV-screening agent (or sunscreen), which may be a chemical screeningagent or a physical blocking agent or a mixture of such screeningagents.

The amounts of the various constituents of the composition according tothe invention are those conventionally used in cosmetics.

Needless to say, a person skilled in the art will take care to selectthe optional additional additives and/or the amount thereof such thatthe advantageous properties of the composition according to theinvention are not, or are not substantially, adversely affected by theenvisaged addition. In particular, these compounds must not harm theadvantageous properties of the DHEA-based compound(s) that may be usedaccording to the invention, or promote its (their) recrystallization.

The composition according to the invention may especially constituteprotective/care/makeup products for the face, the body or the scalp andhaircare products.

The present invention also relates to the cosmetic use of thecomposition mentioned above, for preventing or treating the signs ofintrinsic or photo-induced ageing of the skin.

The invention also relates to the use of the composition mentioned aboveto manufacture a preparation for preventing or treating atrophy of theskin or of mucous membranes.

The invention will now be illustrated with the aid of the non-limitingexamples that follow.

EXAMPLES Example 1 DHEA-Based Niosomes

Sorbitan palmitate 4% Cholesterol 4% Vitamin E acetate 0.5%   DHEA0.5%   Disodium acylglutamate 1% Distilled water qs. 100%Procedure

These vesicles were prepared via the Bangham method.

The vesicles obtained have a mean size of less than 500 nm and show norecrystallization of the DHEA. They may be introduced into an emulsifiedsupport or simply gelled with a hydrophilic polymer of Carbomer or AMPStype.

Example 2 Composition Based on Niosomes Containing DHEA

Diglyceryl distearate 4.5%   Cholesterol 4% DHEA 1% Monosodiumacylglutamate 1% Distilled water qs. 60% Oily phase Capric/caprylictriglyceride 15%  Volatile silicone 10%  Gelling phase Carbomer 0.3%  Preserving agents 1% Distilled water qs. 100% Triethanolamine 0.3%  

The lipid combination is prepared by mixing the constituents under hotconditions. This mixture, cooled to room temperature, is introduced intothe aqueous phase at 90° C. Very vigorous stirring is maintained for 30to 60 minutes. The suspension is then cooled to 60° C. and homogenizedusing a high-pressure homogenizer at 500 bar. A suspension of niosomescomprising DHEA, and with a mean size of less than 300 nm, is obtained.

The oily phase is introduced with vigorous stirring into this vesicularsuspension, which has been cooled to a temperature of 30° C. Thispre-emulsion is homogenized at 500 bar and the whole mixture, oncecooled to 25° C., is then gelled with the gelling phase, which isdispersed using a deflocculator. A shiny, smooth, white cream containing1% DHEA is obtained.

1. A composition comprising a dispersion of an outer aqueous phase, aninner hydrophilic phase and at least one DHEA compound, wherein theouter aqueous phase comprises vesicles of lipid lamellar phasescomprising at least one amphiphilic lipid, wherein the lipid lamellarphases encapsulate the inner hydrophilic phase, wherein the lamellarphases do not comprise a succinic derivative, or a hemisuccinicderivative or both, and wherein the at least one DHEA compound ispresent in the lamellar phases.
 2. The composition according to claim 1,wherein the DHEA compound is selected from the group consisting of DHEA,a DHEA precursor and a DHEA derivative.
 3. The composition according toclaim 2, comprising at least one of Δ5-pregnenolone,17α-hydroxypregnenolone or 17 α-hydroxypregnenolone sulphate.
 4. Thecomposition according to claim 2, comprising at least one DHEA chemicalprecursor selected from the group consisting of a sapogenin, a naturalextract of fenugreek and an extract of a Dioscorea plants
 5. Thecomposition according to claim 2, comprising at least one DHEAderivative selected from the group consisting ofΔ5-androstene-3,17-diol, Δ4-androstene-3,17-dione, 7α-OH DHEA, 7β-OHDHEA, 11α-OH DHEA, 7-keto-DHEA, 3-acetoxy-7-keto-DHEA, DHEA sulphate, ahydroxycarboxylic acid ester of DHEA, DHEA salicylate, DHEA acetate,DHEA valerate, DHEA enanthate, a DHEA carbamate, a 2-hydroxymalonateester of DHEA and an amino acid ester of DHEA.
 6. The compositionaccording to claim 2, comprising a DHEA derivative is represented byformula (1)

in which: R₁ and R₂ are independently: a saturated or unsaturated,linear, branched or cyclic C₁-C₁₂ alkyl group optionally containing oneor more hetero atoms, and optionally substituted with one or more of anOR′, —SR6′, —COOR′, —NR′R′, halogen, sulphate, phosphate, aryl, orheterocycle group, an alkylcarbonyl group, the C₁-C₂₄ alkyl portion ofwhich is saturated or unsaturated, linear, branched or cyclic, andoptionally substituted with one or more of a —OR′, —SR′, —COOR′, —NR′R,halogen, sulphate, phosphate, aryl, or heterocycle group, anarylcarbonyl group, or an arylalkylcarbonyl group, optionallysubstituted with one or more groups of a —OR′, —SR′, —COOR′, —NR′R′,halogen, aryl or heterocycle group; a group O═P(OH)OR′; a group(O)₂SOR′; a trialkylsilyl group of formula SiR′₃ in which the 3 groupsR′ may be identical or different; a carbonyloxyalkyl group of formulaR′OCO; a carbonylaminoalkyl group of formula R′NHCO; in which R′ is ahydrogen atom, a saturated or unsaturated, linear, branched or cyclicC₁-C₁₂ group optionally containing one or more hetero atoms, optionallyfunctionalized with one or more of a —OR″, —COOR″, halogen, —NR″R″, oraryl group, and optionally functionalized with one or more of a —OR″,—COOR″, halogen or —NR″R″ group; R″ representing a hydrogen atom or asaturated or unsaturated, linear, branched or cyclic alkyl chain,wherein each of the groups —NR′R′ and —NR″R″, the substituents R′ or R″,respectively, are identical or different.
 7. The composition accordingto claim 6, comprising 3-O-acetyl-7-benzoyloxy-dehydroepiandrosterone.8. The composition according to claim 1, wherein the DHEA compoundrepresents from 0.1% to 50% by weight of the lipid lamellar phases. 9.The composition according to claim 1, wherein the lamellar phasescomprise at least one nonionic amphiphilic lipid selected from the groupconsisting of an alkyl ester of a polyol, a polyalkyl ester of a polyol,an alkyl ether of a polyol, a polyalkyl ether of a polyol andoxyalkylerated compounds thereof, with a melting point of at least 40°C.
 10. The composition according to claim 9, comprising a nonionicamphiphilic lipid comprising a mixture of polyol esters of at least oneacid with a saturated hydrocarbon-based chain containing at least 14carbon atoms.
 11. The composition according to claim 9, comprising anonionic amphiphilic lipid comprising a polyol ether of at least onealcohol with a saturated hydrocarbon-based chain containing at least 14carbon atoms.
 12. The composition according to claim 9, comprising atleast one nonionic amphiphilic lipid consisting of a mixture of estersof at least one polyol selected from the group consisting of apolyethylene glycol comprising from 1 to 60 ethylene oxide units,sorbitan, sorbitan bearing 2 to 60 ethylene oxide units, glycerolbearing 2 to 30 ethylene oxide units, a polyglycerol comprising 2 to 15glycerol units, a sucrose, a glucose bearing 2 to 30 ethylene oxideunits, and a fatty acid comprising a saturated or unsaturated, linear orbranched C₁₄-C₂₀ hydrocarbon-based chain.
 13. The composition accordingto claim 1, wherein the lamellar phases comprise an ionic amphiphiliclipid.
 14. The composition according to claim 13, wherein the ionicamphiphilic lipid is selected from the group consisting of an alkalimetal salt of dicetyl, an alkali metal salt of dimyristyl phosphate; analkali metal salt of cholesteryl sulphate; an alkali metal salt ofcholesteryl phosphate; a monosodium acylglutamate; a disodiumacylglutamate; a sodium salt of phosphatidic acid; a phospholipids; anacylgutamate, a alkylsulphonic derivative, and an ammonium saltrepresented by formula (II):

in which the radicals R₁ to R₄, which may be identical or different,represent a linear or branched aliphatic radical containing from 1 to 30carbon atoms, an aromatic aryl radical, an aromatic radical, analkylaryl radical; X is an anion selected from the group consisting of ahalide, a phosphate, an acetate, a lactate, a (C₂-C₆)alkyl sulphate, analkyl sulphonate and a alkylaryl sulphonate, an quaternary ammoniumsalts of imidazolinium, represented, by formula (III):

in which R₅ represents an alkenyl or alkyl radical containing from 8 to30 carbon atoms, R₆ represents a hydrogen atom, an alkyl radicalcontaining from 1 to 4 carbon atoms or an alkenyl or alkyl radicalcontaining from 8 to 30 carbon atoms; R₇ represents an alkyl radicalcontaining from 1 to 4 carbon atoms; R₈ represents a hydrogen atom or analkyl radical containing from 1 to 4 carbon atoms; X is an anionselected from the group consisting of a halide, a phosphate, an acetate,a lactate, an alkyl sulphate, and an alkyl sulphonate and an alkylarylsulphonate, and diquaternary ammonium salts represented by formula (IV):

in which R₆ denotes an aliphatic radical containing from 16 to 30 carbonatoms approximately; R₇, R₈, R₉, R₁₀ and R₁₁, which may be identical ordifferent, may be a hydrogen or an alkyl radical containing from 1 to 4carbon atoms; and X is an anion selected from the group consisting of ahalide, an acetate, a phosphate, a nitrate and a methyl sulphate. 15.The composition according to claim 9, wherein the lamellar phasescontain comprise at least one additive selected from the groupconsisting of sterols, fatty-chain alcohols, fatty chain diols,fatty-chain amines and quaternary ammonium derivatives thereof.
 16. Thecomposition according to claim 15, comprising cholesterol.
 17. Thecomposition according to claim 16, wherein the lamellar phases comprisefrom 35% to 90% by weight of nonionic amphiphilic lipid, from 0 to 20%by weight of ionic amphiphilic lipid, from 5% to 50% by weight ofcholesterol and from 0.1% to 50% by weight of the DHEA-compound relativeto the total weight of the lipids comprising the lamellar phase.
 18. Thecomposition according to claim 1, wherein the lamellar phases compriseat least one phospholipids, combined either with cholesterol andoptionally with an ionic surfactant, or with an oxyethylenatedphytosterol comprising from 2 to 50 ethylene oxide units.
 19. Thecomposition according to claim 18, wherein the lamellar phase compriseslecithin.
 20. The composition according to either claim 18, wherein thelipid vesicles comprise from 50% to 99% by weight of lecithin, from 50%to 1% by weight of a mixture of cholesterol and the DHEA compound, andfrom 0 to 20% by weight of one or more ionic surfactant relative to thetotal weight of the lipids comprising the lamellar phase.
 21. Thecomposition according to claim 18 wherein the lipid vesicles comprisefrom 40% to 80% by weight of lecithin and from 20% to 60% by weight of amixture of oxyethylenated phytosterol and the DHEA compound relative tothe total weight of the lipids comprising the lamellar phase.
 22. Thecomposition according to claim 1, wherein the lipids are in the vesiclesand represent from 1% to 20% of the total weight of the composition. 23.The composition according to claim 1 in gel form.
 24. The compositionaccording to claim 1, further comprising an oily phase dispersed in theouter aqueous phase or a phase in which the outer aqueous phase isdispersed.
 25. The composition according to claim 1, comprising at leastone water-soluble, amphiphilic or liposoluble active agent. 26(Canceled). 27 (Canceled).
 28. The composition according to claim 4,comprising at least one sapogenin selected from the group consisting ofdiosgenin, hecogenin, smilagenin, sarsapogenin, tigogenin, yamogenin andyuccagenin.
 29. The composition according to claim 6, wherein at leastone of R₁ or R₂ is a group substituted with a heterocycle group selectedfrom the group consisting of indole, a pyrimidine, a piperidine, amorpholine, a pyran, a furan, a piperazine and a pyridine.
 30. Thecomposition according to claim 1, wherein at least one of R₁ or R₂ is aphenylcarbonyl group.
 31. The composition according to claim 6, whereinat least one of R₁ or R₂ is a benzylcarbonyl group.
 32. The compositionaccording to claim 6, wherein at least one of R₁ or R₂ is substitutedwith a C₁-C₆ alkyl group.
 33. The composition according to claim 6,wherein at least one of R₁ or R₂ is substituted with a R′ groupfunctionalized with a phenyl group.
 34. The composition of claim 6,wherein at least one of R₁ or R₂ is substituted with a R′ group which isfunctionalized with a group containing a R″ group that is a C₁-C₆ alkylchain.
 35. The composition according to claim 1, comprising a DHEAcompound present in an amount of from 1% to 25% by weight of the lipidlamellar phases.
 36. The composition according to claim 18, wherein thelamellar phase comprises hydrogenated lecithin.
 37. The compositionaccording to claim 1, wherein the lipids are in vesicles and the lipidsare present in an amount of from 1% to 10% of the total weight of thecomposition.
 38. A cosmetic method comprising administering thecomposition of claim 1 to a mammal to prevent or treat the signs of atleast one of intrinsic aging of the skin or photo-induced aging of theskin.
 39. A composition comprising the composition of claim 1 and aphysiologically or dermatologically acceptable diluent, excipient orcarrier.